Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)

Peter Jurutka, Ichiro Kaneko, Joanna Yang, Jaskaran S. Bhogal, Johnathon C. Swierski, Christa R. Tabacaru, Luis A. Montano, Chanh C. Huynh, Rabia A. Jama, Ryan D. Mahelona, Joseph T. Sarnowski, Lisa M. Marcus, Alexis Quezada, Brittney Lemming, Maria A. Tedesco, Audra J. Fischer, Said A. Mohamed, Joseph W. Ziller, Ning Ma, Geoffrey M. GrayArjan Van Der Vaart, Pamela Marshall, Carl Wagner

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Original languageEnglish (US)
Pages (from-to)8432-8454
Number of pages23
JournalJournal of Medicinal Chemistry
Volume56
Issue number21
DOIs
StatePublished - Nov 14 2013

Fingerprint

Retinoid X Receptors
Benzoic Acid
Cutaneous T-Cell Lymphoma
Retinoic Acid Receptors
Drug Design
Tretinoin
bexarotene
CD 3254
acrylic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists : Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254). / Jurutka, Peter; Kaneko, Ichiro; Yang, Joanna; Bhogal, Jaskaran S.; Swierski, Johnathon C.; Tabacaru, Christa R.; Montano, Luis A.; Huynh, Chanh C.; Jama, Rabia A.; Mahelona, Ryan D.; Sarnowski, Joseph T.; Marcus, Lisa M.; Quezada, Alexis; Lemming, Brittney; Tedesco, Maria A.; Fischer, Audra J.; Mohamed, Said A.; Ziller, Joseph W.; Ma, Ning; Gray, Geoffrey M.; Van Der Vaart, Arjan; Marshall, Pamela; Wagner, Carl.

In: Journal of Medicinal Chemistry, Vol. 56, No. 21, 14.11.2013, p. 8432-8454.

Research output: Contribution to journalArticle

Jurutka, P, Kaneko, I, Yang, J, Bhogal, JS, Swierski, JC, Tabacaru, CR, Montano, LA, Huynh, CC, Jama, RA, Mahelona, RD, Sarnowski, JT, Marcus, LM, Quezada, A, Lemming, B, Tedesco, MA, Fischer, AJ, Mohamed, SA, Ziller, JW, Ma, N, Gray, GM, Van Der Vaart, A, Marshall, P & Wagner, C 2013, 'Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)', Journal of Medicinal Chemistry, vol. 56, no. 21, pp. 8432-8454. https://doi.org/10.1021/jm4008517
Jurutka, Peter ; Kaneko, Ichiro ; Yang, Joanna ; Bhogal, Jaskaran S. ; Swierski, Johnathon C. ; Tabacaru, Christa R. ; Montano, Luis A. ; Huynh, Chanh C. ; Jama, Rabia A. ; Mahelona, Ryan D. ; Sarnowski, Joseph T. ; Marcus, Lisa M. ; Quezada, Alexis ; Lemming, Brittney ; Tedesco, Maria A. ; Fischer, Audra J. ; Mohamed, Said A. ; Ziller, Joseph W. ; Ma, Ning ; Gray, Geoffrey M. ; Van Der Vaart, Arjan ; Marshall, Pamela ; Wagner, Carl. / Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists : Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254). In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 21. pp. 8432-8454.
@article{959b913a8e1f42a0bf7a1a63deffcd76,
title = "Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)",
abstract = "Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.",
author = "Peter Jurutka and Ichiro Kaneko and Joanna Yang and Bhogal, {Jaskaran S.} and Swierski, {Johnathon C.} and Tabacaru, {Christa R.} and Montano, {Luis A.} and Huynh, {Chanh C.} and Jama, {Rabia A.} and Mahelona, {Ryan D.} and Sarnowski, {Joseph T.} and Marcus, {Lisa M.} and Alexis Quezada and Brittney Lemming and Tedesco, {Maria A.} and Fischer, {Audra J.} and Mohamed, {Said A.} and Ziller, {Joseph W.} and Ning Ma and Gray, {Geoffrey M.} and {Van Der Vaart}, Arjan and Pamela Marshall and Carl Wagner",
year = "2013",
month = "11",
day = "14",
doi = "10.1021/jm4008517",
language = "English (US)",
volume = "56",
pages = "8432--8454",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

TY - JOUR

T1 - Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists

T2 - Novel analogues of 4-[1-(3,5,5,8,8- Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl) -4-hydroxyphenyl)acrylic acid (CD3254)

AU - Jurutka, Peter

AU - Kaneko, Ichiro

AU - Yang, Joanna

AU - Bhogal, Jaskaran S.

AU - Swierski, Johnathon C.

AU - Tabacaru, Christa R.

AU - Montano, Luis A.

AU - Huynh, Chanh C.

AU - Jama, Rabia A.

AU - Mahelona, Ryan D.

AU - Sarnowski, Joseph T.

AU - Marcus, Lisa M.

AU - Quezada, Alexis

AU - Lemming, Brittney

AU - Tedesco, Maria A.

AU - Fischer, Audra J.

AU - Mohamed, Said A.

AU - Ziller, Joseph W.

AU - Ma, Ning

AU - Gray, Geoffrey M.

AU - Van Der Vaart, Arjan

AU - Marshall, Pamela

AU - Wagner, Carl

PY - 2013/11/14

Y1 - 2013/11/14

N2 - Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

AB - Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8- tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6- pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

UR - http://www.scopus.com/inward/record.url?scp=84887928768&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887928768&partnerID=8YFLogxK

U2 - 10.1021/jm4008517

DO - 10.1021/jm4008517

M3 - Article

C2 - 24180745

AN - SCOPUS:84887928768

VL - 56

SP - 8432

EP - 8454

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -